Abstract 6056: Activation of Sting in response to partial-tumor radiation exposure
Authors: Mickael Mathieu, Prerna R. Nepali, Sadna Budhu, Simon N. Powell, John Humm, Joseph Deasy, Adriana Haimovitz-Friedman
Journal: Cancer Research (2022)

Abstract Purpose: It has been shown that ionizing radiation can mediate antitumor immunity via the activation of the cytosolic DNA sensor cGAS/STING pathway. Therefore, the purpose of this study was to determine whether STING activation is involved in partial volume radiation therapy (RT). Materials/Methods: We investigated 67NR murine orthotopic breast tumors in Balb/c mice and LLC cells injected in the flank of C57Bl/6, cGAS, or STING KO mice. RT was delivered to 50% or 100% of the tumor volume using a 2X2 cm collimator on a microirradiator allowing precise irradiation. Tumors were collected at different time points post-RT and assessed for different measurements. Results: We previously showed that a single dose of radiation delivered to half of the tumor (50% RT) activated an anti-tumor immune response comparable to the response in a fully-irradiated tumor in the immunogenic 67NR murine breast carcinoma tumor model and in the less immunogenic and more radioresistant Lewis lung carcinoma (LLC) tumor model. We have also demonstrated that this immune response was due to the infiltration of CD8+ T cells along with an increased expression of ICAM adhesion molecules. Treatment with either anti-CD8 or anti-ICAM antibodies abrogated the hemi-RT response. Furthermore, a significant abscopal effect was observed after partial irradiation with a single dose of 10Gy in a bilateral 67NR tumors model. In this study, we tested whether the hemi-irradiation-mediated immune response involves the cGAS/STING canonical pathway, or a non-canonical activation of STING, in the 67NR or LLC tumor models. It has been reported that STING can be activated, independently of cGAS, via non-canonical activation of STING, involving ATM and TRAF6, among other factors. We found significant activation of the cGAS/STING pathway in the hemi-irradiated tumors as compared to control and to 100% exposed 67NR tumors. Interestingly, the increased expression of the cGAS/STING pathway was found in the hemi-irradiated tumor but, also in the non-irradiated part of this hemi-irradiated tumor. In the LLC model, a non-canonical activation of STING was involved. Using both cGAS and STING KO mice, we demonstrated that the partial exposure RT-mediated immune response is dependent on STING activation in the host while cGAS is dispensable. Conclusions: Upstream pathways responsible for STING activation are tumor type-specific. Identifying the upstream pathways responsible for STING activation in the partial RT-mediated immune response in different tumor types would improve this therapy and its potential combination with immune checkpoint blockade. Citation Format: Mickael Mathieu, Prerna R. Nepali, Sadna Budhu, Simon N. Powell, John Humm, Joseph Deasy, Adriana Haimovitz-Friedman. Activation of Sting in response to partial-tumor radiation exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6056.